Abstract

The increasing prevalence and incidence urge efficient treatment of osteoarthritis (OA). In contrast, a single modality is hard to combat OA's complicated pathogenesis and achieve comprehensive chondroprotective function. Through RNA sequencing, we identified bone marrow mesenchymal stromal cell-derived exosomes (BMSC-Exo) and cartilage progenitor cell-derived exosomes (CPC-Exo) have distinct enrichment of miRNA contents, emphasizing macrophage and chondrocyte modulation, respectively. Thus, inspiring us to develop a bi-exosome combination strategy, which combines anti-inflammatory BMSC-Exo and anti-catabolic CPC-Exo, to alleviate osteoarthritis progression via simultaneous regulation of macrophage polarization and chondrocyte phenotype. Once delivered into the rat knee joint cavity by hyaluronic acid methacryloyl microspheres, the bi-exosome combination remarkably postponed OA progression via combating the joint inflammatory and catabolic environment, in which the dominant interventive pathways ( i.e. , miR-708–5p/NRP-1, miR-431/BRCA-1/PLK-1, and miR-7a-5p/NOTCH-3) were further revealed. This work presents the tailoring of exosome compositions to modulate multitargeting, thereby creating a potential for OA treatment.